Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Begrippenlijst TOX30306 Food Supplements - Upper intake level (UL): Maximum level of intake that is physically tolerable in such a way that no adverse effects occur in humans. - Difference UL and ADI: UL is the maximum level of intake that is physically tolerable in such a way that no adverse effects occur in humans. ADIs are derived from NOAELs, ULs cannot be derived from NOAELs since then intake levels might be lower than the reference daily intake. - Annex I: List of compounds which may be used in vitamin and mineral supplements and the tolerable upper intake levels of each compound. - Annex II: List of substance that may be used to manufacture vitamin and minerals. - List of safety evaluation points for vitamins and minerals: - Nutrients are essential for human well-being within a certain range of intakes - There is a long history of safe consumption - Some nutrients may be consumed chronically at levels of significantly above those obtained from endogenous nutrients in foods without reported adverse effects. - Data on adverse effects in humans may help reduce uncertainty factors - Protection is present against nutrients through homeostatic regulation, such as excretion or absorption. - A tolerable upper intake level is present. This is the maximum level of total chronic daily intake of a nutrient which is judged to be unlikely to produce a risk of adverse health effects. - Concerns of Food plants supplements: - Overconsumption - Natural is equal to safe for consumers - Availability of harmful plant food supplements - Often no requirement of proven safety of PFS - Toxicity of PFS caused by: - Naturally present toxic ingredients - Harmless ingredients may be replaced with a toxic alternative - Adulteration (deliberately adding illegal compounds) - Contamination of harmful compounds Naturally present compounds: - Pyrolizidine alkaloids (PA): Cause obstruction of small veins in liver (hepatoxicity) and cancer In animals - Alkenylbenzenes: Present in PFS containing oil of basil, fennel, nutmeg and more. Cause liver tumours (genotoxocity) in rodents at high levels. Replacement of harmless ingredients with toxic alternative: - Anisatin in Japanese star anise is not present in Chinese star anise: Inhibits GABA causing epileptic abnormalities - Aristolochic acids: - Causing cardiovascular damage, kidney damage and cancer in kidneys and urinary tract. Adulteration - Sibutramine: - Increased risk of adverse cardiovascular events - Sildenafil - Increased risk on skincancer Contaminants Polycyclic aromatic hydrocarbons (PAH) Benzo [a] pyrene: - Genotoxic carcinogenic - EFSA Tiers: Used to assess PFS on risk for adverse effects. - EFSA Tier 1: Nature of preparation Its tended uses and levels of use Whether the preparation has long history of no adverse effects. - EFSA Tier 2: For botanical compounds lacking a history of food use, or levels of use exceed historical intake levels. This compound needs an ADI, TDI or TTC or MOE. - Labels of PFS: - Indication of nature of ingredients - Recommended daily intake and warning of risks to health if this is exceeded - Is not a substitute for varied diet - Not a medicinal product - Should be out of reach of young children - Most not contain a statement that it can cure, prevent or treat diseases - Any statement that a varied diet cannot provide the appropriate quantities - Any misleading claims -> elimination from the market. Natural toxins Glycosides Are bioactive compounds that have a sugar attached to the part which is responsible for the toxic action. Aglycon is such a toxic compound in a glycoside. Aglycon has potential to decrease bone loss in post-menopausal woman. (Also called genistein). Improper preparation Anti-Nutritional factors (ANF) Trypsin inhibitors: Inhibit with protein digesting enzymes Lectins Interfere with absorption nutrients in intestine Solanine Inhibits acetylcholinesterase, preventing breakdown of neurotransmitter acetylcholine. Leading to irritation and injury of GI tract, abdominal cramps, vomiting, diarrhae, weakness and unconsciousness Famine foods Cyanogenic glycosides May release hydrogen cyanide (HCN). HCN inhibits cytochrome c (Complex IV of OXPHOS) ultimately causing the paralytic disease Konzo. HCN detoxification creates thiocyanate, which inhibits iodide uptake in the thyroid and leads to swelling of the neck. Toxic amino acid: Lathyrogens Grass pea (lathyrus sativus): Oxalyldiaminopropionic acid (ODAP) is the active compound which causes muscle weakness, stiffness and paralysis of leg muscles (neurotoxicity). Due to overstimulation of the glutamate receptor. ODAP -> Neurolathyrism Sweet pea (lathyrus odoratus): Beta-aminopropionitrile (BAPN) is the active compound that causes weak connective tissue due to inhibition of formation of cross connections between collagen and elastin BAPN -> Osteolathyrism Supplements Glucosinolates: Isothiocyanates: claimed to have anti-cancer properties through induction of protective enzymes. But might be genotxic themselves Alkenylbenzenes: Genotoxic and carcinogenic. Sensitive individuals Fava glycosides: Vicine and convicine: Initiate low levels of G6PD, leading to low levels of gluthathione (GSH), leading to lack of protection against oxidative stress which affects red blood cells. Herbal teas Pyrrolizidine alkaloids Liver necrosis, liver cancer, liver damage Phytoestrogens Genistein Disrupt the reproductive performance due to properties similar to 17B-estradiol. Natural toxins in animals Bacterial toxins Clostridium botulinum Inhibits rlease of acetylcholine in presynaptic membrane of motor endplates. Leading to weakness of muscles, due to botulinum toxin which can be fatal. Fycotoxins (marine algae) Dinoflagellates Group of flagellate eukaryotic organisms which accumulate in the food chain. Saxitoxic: Paralytic shellfish posion Blocks Na-Influx, resulting in nausea, vomiting, diarrhoea, numbness, tingling lips, coordination probelsm, confusion, paralysis, respiratory distress and death. Brevetoxin: Neurotoxic shellfish posion Activates sodium channel by enchancement of Na-permeability. Leading to nausea, vomiting, diarrhoea, numbness, tingling lips, coordination problems, confusion But NO paralysis, respiratory distress or death. Ciguatoxin: Ciagatura fish posion Enhances Na permeability to activate sodium channels. Leading to nausea, vomiting, diarrhoea, numbness, tingling lips, coordination problems, confusion But NO paralysis, respiratory distress or death. Domoic acid: Amnesic shellfish poison Overstimulates glutamate neurons, leading to neurotoxicity. High intracellular calcium levels cause neuronal cell death, lesions in areas of the brain. Okadaic acids: Diarrhetic shellfish poison Inhibits ser/thr protein phosphatases leading to hyperphosphorylation of proteins. Including ion channels in intestinal epithelia, resulting in impaired water balance and loss of fluids. Fish toxins Tetrodotoxin Neurotoxin by blocking sodium channels causing paralysis and death Scombrotoxins Fish rich in histidine, which leads to an allergic reaction. Scombroid fish. Food additives Reasons additives are added - To maintain product consistency - To improve or maintain nutritional value - To maintain pleasure experience & wholesomeness - To regulate pH - To enhance flavour or change colour Direct additive - For specific purpose added Indirect additive - Unintentionally though predictably becomes part of food (packaging). Evidence needed to become European recognised additive: - performs as intented - will not cause adverse health effects - Usage does not mislead consumer Nitrosamine Nitrate is added to food as additive to kill Clostridium and prevent product of botulinum. But nitrate with amines can form nitrosamine and cause stomach cancer. Classification of additives based on carcinogenicity Group 1: carcinogenic to man -> forbidden Group 2A: Probably carcinogenic -> forbidden Group 2B: Possibly carcinogenic -> more research Group 3: Compound cannot be classified because of insufficient data -> more research Group 4: Proven to be non-carcinogenic for humans Southhampton study conclusions EFSA: - Limited consistency with respect to age and gender of children and the different mixtures. - Unknown relevance of the effect observed. - Lack of information on dose-reponse - Lack of a biologically plausible mechanism - Use of mixture of compounds, instead of single compounds - Observer bias of teachers, parents and classroom observers Food allergy types Type 1 = hypersensitivity -> release of histamine and cytokines by mast cells when allergen is encountered. Type 4 = Delayed hyper sensitivity -> macrophages present allergens to T-cells, cells release interleukins, which stimulates the immune system and cause inflammation. Acetyl saliculic acid sensitivity Interference with prostaglandin synthesis. Leading to urticarial (netelroos), angioneurotic oedema, rhinitis, asthma and hyperkinesis. AZO-dyes Are frequently associated with hypersensitivity. Tartrazine Is an AZO dye suspected of causing hypersensitivity. Sulfite suspected of causing asthmatic like allergic reactions. Biotransformation Bioavailability depends on 5 steps Liberation from GI tract Transport across intestinal membrane Blood circulation and distribution Metabolism or biotransformation Excretion Metabolism of xenobiotics Phase 1: Modification: Reaction: Oxidation, reduction and hydrolysis Product: Polar metabolite with functional OH, NH2, SH, COOH group Cofactor: NADPH Phase2: Conjugation: Enzyme: Epoxide hydrolase, glutathione S-transferase, glucuronosyntransferase and sulfotransferase. Product: Hydrophilic metabolites Conjugation with: Water, glutathione, glucuronic acid and sulfate Measurement of biotransformation Mix of compound, cofactor, S9/microsomes(for biotransformation) is incubated and measured. Abundance of P450 CYP1A2 isoenzymes differ with Age Gender Lifestyle; smoking, grapefruit juice or barbecue meat consumption Genetics Chemicals Acrylamide Formed during heating, through sugars and asparagine. Is carcinogenic, neurotoxic, reduces fertility. Anethole Flavoring substance Aspartame Only dangerous for PKU patients because of phenylalanine, which they cannot breakdown and can cause brain damage in high concentrations. Dioxin Accumulates in fat, toxic in low doses. Slow metabolism and elimination. Is thought to decrease sperm count and cause liver tumours at higher dose levels. TCDD Is a dioxin, which is thought to decrease sperm count and cause liver tumours at higher dose levels. PCB Is a dioxin, which is thought to decrease sperm count and cause liver tumours at higher dose levels. BDE-47 BDE-47 accumulates in fat because it is hardly broken down and bioaccumulates. Is potential health treat. Bisphenol A Present in a lot of stuff. In high numbers may cause infertility and harm the hormone system. Butyl benzyl phthalate (BBP) Present in a lot of stuff. In high numbers may cause infertility and harm the hormone system. Chloramphenicol Antibiotic which is not used. Adverse effects: anemia, leukemia, bone marrow suppression, nausea and diarrhea. Coumarin Compound present in plants. Chronic exposure leads to liver damage, reduced blood clotting and carcinogenic. Curcumin Colouring compound. It thought to have positive effect on cancer, diabetes. Anticarcinogenic Metals Methylmercury Converted to MeHg by microorganisms. Ccumulated by fish. Can cause neuro(developemental) adverse effects, through increased intracellular calcium, cell death and ROS. Lead Inhibits heme synthesis leading to anemia. Initiates demyeliation, leading to neuro toxicity, through disturbance of calcium homeostasis and ROS. Can accumulate in bones in which the half life increases drastically. Cadmium Nephrotoxicity and osteoporosis. When metallothionein (chelator) binding saturates severe kidney damage occurs, through ROS, calcium loss and bone loss. Subgroups such as children, smokers, vegetarians and people living in areas rich in cadmium are more vulnerable. Arsenic Genomic instability due to decrease of global methylation leading to cancer risk. Especially skin cancer. Chelators Methallothionein Ethylene-diamino-tetra-cetic-acid Dimercaptopropanol Veterinary drugs MRL Maximum residue level of pesticides. Forazolidone Widely used in pigs and chickens. Mutagenic and carcinogenic so no NOAEL. Its quickly broken down, metabolites aswell. But mouse studies proven opposite so not risk taken and banned. B-agonist More meat, less fat. But affects human heart so its prohibited. Combination toxicology Complex vs. Simple mixtures Complex mixture > 10 compounds Simple mixture < 10 compounds Simple similar action No interaction, similar mode of action Simple dissimilar action No interaction, different mode of action Interaction Potentiation or antagonism Response addition Summation of effect A and B Dose addition Summation of doses A and B Oxidants Reactive oxygen species: - Superoxide anion radical - Hydroxyl radical - Hydrogen peroxide - Singlet oxygen Sources of ROS - Decoupling one-electron transport chains - Enzymatic reaction - Redox cycling (paraquat) - Inflammation neutrophils/macrophages - From other ROS (Haber-Weiss reaction) Damage produced by ROS - Oxidation proteins/enzymes -> loss of function - Oxidation of DNA -> mutagenicity and carcinogenicity - Oxidation unsaturated fatty acids -> lipid peroxidation (disturbs membrane structure) Antioxidants - Vitamin C - Vitamin E - Carotenoids - GSH (glutathione) - Ubiquinone coenzyme Q10 - Polyphenols Antioxidant enzymes - Superoxide dismutase (SOD) - Catalase - Glutathione peroxidase Natural anti-oxidants - Carotenoids - Vitamin E - Vitamin C - Polyphenols like flavonoids - Peptides (glutathione) - Conjugated linoleic acid - Coenzyme Q (ubiquinine) These can donate e- or H+ or form a stable AOX radical. Antioxidants Plasma level which adverse effect 4-5 times Reasons beta-carotene supplementation may increase risk on long cancer - Reactive beta carotene metabolites - Disturbing retinal signalling, thereby activating oncogenes and down regulating tumour suppressor genes Sint janskruid decreased P450 efficiency, leading to decreased medicines efficiency. Polyphenols (quercetin) health claims; inhibition of cancer, ageing, cardiovascular disease and photosensitivity diease. At high levels more indicdence of tumors. Flavourings Three types of flavourings - Flavour substance which are chemically identified - Flavour preparation from plant or animal origen (natural flavour complexes) - Thermal process flavour or smoke flavours Ames test Salmonella Thyphimurium cannot form colonies due to absence of external amino acid source, unless reversion of the mutation restores biosynthesis of the amino acid. TK test Mammalian gene mutation test (TK). TK+/- (non mutated) die, whilst TK-/- survive. So mutation is needed to survive Chromosome aberration test (CAT) Chinese hamster ovary cells or human lymphocytes. Arrest cells in metaphase, then after exposure to compound examine structural changes in chromosomes. Flavours are grouped in 3 classes: Class 1: flavours have simple chemical structure, suggesting low oral toxicity Class 2: flavours have less innocent structures, but are not suggestive of toxicity Class 3: may suggest toxicity, or have structural features that permit no strong initial presumption of safety. The Threshold of toxicological concern (TTC) is used. Class 1 – 1800ug/day Class 2 – 540 ug/day Class 3 – 90 ug/day Diacetyl flavour giving buttery flavour. Inhalation is dangerous, however the safety evaluaton is only for oral exposure. Couramin is not genotixic, but is carcinogenic. So a thresholded mode of action. Alkenylbezenes is genotixic, restricted in the EU. Nanotoxicology Uptake in intestine - Transcellular through normal intestinal enterocytes. - Paracellular (between enterocytes through tight junctions). - Peyers patches lymphatic tissue containing M cells. These M cells take up, process and present the nano-particles to the immune system. Uptake depends on: - Particle size - Surface charge (positively charged become trapped in negatively mucus) (negatively pass right through). - Attachment of ligands - Coating with surfactants Possible health hazard: - ROS production (which can affect membranes typically) - Frustrated phagocytosis - Fibrosis and risk on GI carcinomas - Systematic effect: particles can be transported via nerves. Interleukines may be important for systematic effect (inflammation effect and fibrosis of GI tract). Safety assessment: - Precautionary principle: nothing can changes, if they imply risks for humans or environment. Even if this risk is not proven yet. - Proportionality principle: measures taken should be based on risk-benefit evaluation. Pesticides Exceedance can result from - Unauthorised pesticides - Pesticides not authorised for a specific crop - Higher application rate or shorter pre-harvest intervals - Insufficient washing out Organophates - Inhibit acetylcholinesterase - Leads to overstimulation of postsynaptic receptors.